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AbstractAllogeneic hematopoietic stem cell transplantation (AHSCT) is currently the only treatment modality that is capable of curing myelofibrosis (MF). Although outcomes of AHSCT have improved vastly in recent years owing to advancements in HLA typing, conditioning regimens, and supportive care, it remains a procedure with a considerable risk in MF patients due to conditioning regimen related toxicity, higher rates of graft failure, infections, and graft versus host disease (GVHD). Recent progress in the treatment and prevention of GVHD with post-transplant cyclophosphamide has also rendered transplantation from alternative donors feasible and safer, thus improving access to patients without HLA-identical donors. Accordingly, all patients with intermediate or high-risk MF today should be referred for potential transplant evaluation to consider the pros and cons of an early versus a delayed transplant strategy. Individual risk assessment in MF is best facilitated by contemporary prognostic models that incorporate both clinical and genetic risk factors. The current review highlights new information regarding risk stratification in MF, anchored by practical algorithms that facilitate patient selection for specific treatment actions, including AHSCT. [ABSTRACT FROM AUTHOR]

Aim: To estimate projected US-based cost and time burden for patients with myelofibrosis and anemia treated with momelotinib compared with danazol. Methods: Cost and time burden were calculated based on the transfusion status of patients in the MOMENTUM trial and estimates extracted from previous studies. Results: Reductions in transfusion associated with momelotinib are projected to result in cost and time savings compared with danazol in transfusion-dependent and transfusion-independent/requiring patients with myelofibrosis, respectively: annual medical costs ($53,143 and $46,455 per person), outpatient transfusion costs ($42,021 and $8,370 per person) and annual time savings (173 and 35 h per person). Conclusion: Fewer transfusions with momelotinib are projected to result in cost and time savings in patients with myelofibrosis and anemia compared with danazol. Plain Language Summary Estimated cost & time savings in patients with the blood cancer myelofibrosis Myelofibrosis is a rare blood cancer often associated with bone marrow damage, too few of some types of blood cells and symptoms including tiredness, night sweating, itching and feelings of fullness and pain because of increased spleen size. Patients with anemia (too few red blood cells) may require regular blood transfusions and this is one sign that myelofibrosis is getting worse. MOMENTUM was a Phase III clinical trial showing that the drug momelotinib was safe and effective in patients with myelofibrosis who were previously treated with a type of drug called a JAK inhibitor. In particular, the trial showed that momelotinib reduced the need for transfusions compared with danazol, another drug typically used to treat patients with anemia. Based on this transfusion information from MOMENTUM and other publicly available information about estimated medical costs and patients' time spent in receiving transfusions, the analysis described here shows that a reduction in the number of transfusions with momelotinib compared with danazol is estimated to lead to cost savings as well as reduced patient time spent in transfusion-related travel, preparing and waiting for transfusions and receiving and recovering from transfusions. Tweetable Abstract Reductions in transfusions associated with momelotinib are projected to result in savings in medical and transfusion-related costs and time burden relative to danazol in patients with myelofibrosis and anemia. Article highlights Momelotinib is a JAK1, JAK2 and ACVR1 inhibitor that targets both the complex drivers of iron-restricted anemia and chronic inflammation in MF, thereby improving constitutional symptoms and splenomegaly while also maintaining or improving Hb levels across the continuum of JAK inhibitor–naive and previously JAK inhibitor–treated patients. Transfusion dependency and moderate-to-severe anemia are critical negative prognostic factors in MF and lead to significantly higher rates of HCRU and costs in affected patients compared with non-TD patients. MOMENTUM is a randomized, double-blind study comparing momelotinib and danazol in symptomatic patients with MF and anemia who previously received JAK inhibitor therapy. Projected differences in cost and time burden associated with momelotinib relative to danazol were based on patient transfusion data from the MOMENTUM trial and cost estimates from studies using the IBM MarketScan Commercial Database and Medicare fee-for-service database as well as time burden estimates from the 2022 Knoth et al. study. Reductions in transfusions associated with momelotinib are projected to result in savings in medical and transfusion-related costs and patient time savings relative to danazol in patients with baseline TD and TI/TR status, respectively, using a terminal TI rate: annual medical costs ($53,143 and $46,455 per person), outpatient transfusion costs ($42,021 and $8,370 per person) and time savings (173 and 35 h per person). Projected savings in total annual medical costs with momelotinib relative to danazol were also shown using a rolling TI rate in patients with baseline TD and TI/TR status ($23,780 and $39,305). Projected savings in transfusion-related costs and patient time savings with momelotinib relative to danazol were also observed for patients aged ≥65 years. The results of this analysis demonstrate that momelotinib not only addresses a high unmet need in patients with MF-associated anemia but may also provide medical cost and time savings for patients by reducing their transfusion dependency. [ABSTRACT FROM AUTHOR]

The document discusses the association between high red cell mass (RCM) and high plasma volume with thrombotic risk in polycythemia vera (PV) patients. The study included 211 PV patients from Serbia and Croatia and found that patients with both high RCM and high plasma volume had the highest risk of thrombotic events. The findings suggest that RCM and plasma volume measurements may be important for prognostic purposes in PV, highlighting the need for further research and validation of these results in larger datasets and different populations. [Extracted from the article]

Ruxolitinib (RUX), a Janus kinase 2 (JAK2) inhibitor, and lenalidomide (LEN), an immunomodulatory agent, have recently been proposed as a combined treatment for myelofibrosis (MF). This combination has demonstrated improved efficacy, safety, and tolerability compared to monotherapy. To further refine these findings, an efficient analytical tool is needed to simultaneously determine RUX and LEN concentrations in blood plasma. This tool would enable the study of their pharmacokinetics, drug-drug interactions, and therapeutic monitoring during MF therapy. Unfortunately, such a method has not been existed in the literature. This study presents the first HPLC method with UV detection for the simultaneous quantitation of RUX and LEN in plasma. The method was validated according to the ICH guidelines for bioanalytical method validation. It exhibited linearity in the concentration ranges of 10 to 3150 ng mL− 1 for RUX and 80 to 5200 ng mL− 1 for LEN. The limits of quantitation were determined to be 25 and 90 ng mL− 1 for RUX and LEN, respectively. All other validation parameters were satisfactory. The HPLC-UV method was successfully employed to study the pharmacokinetics and drug-drug interactions of RUX and LEN in rats following oral administration of single doses. The results demonstrated that the pharmacokinetics of both drugs were changed substantially by their coadministration. LEN exhibited synergistic effects on the maximum plasma concentration (Cmax) and total bioavailability of RUX, meanwhile it exhibited diminishing effect on the values of volume of distribution (Vd) and clearance (CL). Additionally, RUX decreased the Cmax and total bioavailability of LEN, meanwhile it increased its Vd and CL. These data suggest that the use of RUX, as a combination with LEN, is a better therapeutic approach for MF, compared with RUX as a monotherapy. The effects of LEN on the pharmacokinetics of RUX should be considered and can be useful in determining the appropriate RUX dosage and dosing regimen to achieve the desired therapeutic effect when used as a combination therapy with LEN. The method's environmental friendliness was confirmed through three comprehensive tools. This method represents a valuable tool for determining the appropriate dosage and dosing regimen of RUX in combination therapy with LEN to achieve the desired therapeutic effect. Furthermore, it can aid in predicting drug distribution in different patients and assessing the drug accumulation or insufficient drug levels in specific body compartments. [ABSTRACT FROM AUTHOR]

Objectives: There is limited data on the incidence, prevalence, and treatments for myelofibrosis (MF) in Germany. This retrospective study examined claims data from 3.3 million insured individuals, spanning from 2010 to 2021. Methods: Four sensitivity scenarios were explored to identify cases of MF. Point prevalence and cumulative incidence of MF were determined as of December 31, 2021, and within 2021, respectively. A cross‐sectional analysis used the main scenario definition of MF to identify cases and evaluate the period prevalence of patients receiving treatment for symptoms and/or splenomegaly, including first‐line (1L) Janus kinase inhibitor (JAKi), second‐line, or further (2L+) MF‐related treatment therapies during 2021. The prevalence of anemia treatment was also reported. Results: The estimated standardized point prevalence of MF on December 31, 2021, was 9.9–12.4 cases per 100 000 persons, and cumulative incidence in 2021 was 1.2–1.8 cases per 100 000 persons. Standardized period prevalence in 2021 for MF patients receiving 1L JAKi and/or 2L+ MF‐related treatment was 4.0 cases per 100 000. Among these patients, 47.1%–53.7% required treatment for anemia, resulting in a period prevalence of 1.9–2.2 cases per 100 000 individuals. Conclusion: The data reveal gaps in MF treatments and the need to improve patient quality of life. [ABSTRACT FROM AUTHOR]

Inflammation plays a pivotal role in the pathogenesis of primary and post-essential thrombocythemia or post-polycythemia vera myelofibrosis (MF) in close cooperation with the underlying molecular drivers. This inflammatory state is induced by a dynamic spectrum of inflammatory cytokines, although recent evidence points to the participation of additional soluble inflammatory mediators. Damage-associated molecular patterns (DAMPs) represent endogenous signals released upon cell death or damage which trigger a potent innate immune response. We assessed the contribution of two prototypical DAMPs, HMGB1 and S100A8/A9, to MF inflammation. Circulating HMGB1 and S100A8/A9 were elevated in MF patients in parallel to the degree of systemic inflammation and levels increased progressively during advanced disease stages. Patients with elevated DAMPs had higher frequency of adverse clinical features, such as anemia, and inferior survival, suggesting their contribution to disease progression. Monocytes, which are key players inMF inflammation, were identified as a source of S100A8/A9 but not HMGB1 release, while both DAMPs correlated with cell death parameters, such as serumLDH and cell-free DNA, indicating that passive release is an additional mechanism leading to increased DAMPs. HMGB1 and S100A8/A9 promote inflammation through binding to Toll-like receptor (TLR) 4, whereas the former also binds TLR2. Monocytes from MF patients were shown to be hyperactivated at baseline, as reflected by higher CD11b and tissue factor exposure and increased expression levels of proinflammatory cytokines IL-1b and IL-6. Patient monocytes showed preserved TLR4 and TLR2 expression and were able to mount normal or even exacerbated functional responses and cytokine upregulation following stimulation of TLR4 and TLR2. Elevated levels of endogenous TLR ligands HMGB1 and S100A8/A9 coupled to the finding of preserved or hyperreactive TLR-triggered responses indicate that DAMPs may promote monocyte activation and cytokine production in MF, fueling inflammation. Plasma IL-1b and IL-6 were elevated in MF and correlated with DAMPs levels, raising the possibility that DAMPs could contribute to cytokine generation in vivo. In conclusion, this study highlights that, in cooperation with classic proinflammatory cytokines, DAMPs represent additional inflammatory mediators that may participate in the generation of MF inflammatory state, potentially providing novel biomarkers of disease progression and new therapeutic targets. [ABSTRACT FROM AUTHOR]

Background: Segregated-nucleus-containing atypical monocytes have recently been identified in mice. Segregated-nucleus-containing atypical monocytes are thought to originate from the bone marrow and induce fibrosis in the drug-injured lung. The Lyc6c− murine monocyte subset is the counterpart to human CD14−CD16++ non-classical monocytes; however, the human counterpart to murine segregated-nucleus-containing atypical monocytes has not yet been identified. Primary myelofibrosis is a well-known disease of progressive marrow fibrosis, and atypical megakaryocytes are thought to be closely related to fibrosis in primary myelofibrosis bone marrow. However, recently, monocytes have been reported to play an important role in marrow fibrosis in primary myelofibrosis. We speculated that, if there is a human counterpart to murine segregated-nucleus-containing atypical monocytes, it would present the same markers as murine segregated-nucleus-containing atypical monocytes, such as CD14−CD16+ macrophage-1 antigen (CD11b/CD18 complex)+, MSR1+, and CEACAM1+, and it might exist in the bone marrow of patients with primary myelofibrosis. Case presentation: A 74-year-old Japanese male visited our hospital for clinical follow-up after total prostatectomy for prostatic cancer. Anemia, thrombocytosis, and elevated lactate dehydrogenase were suddenly observed in a periodic examination. CALR mutation type 2 (p.K385fs*47) was observed. The histological features of the patient's bone marrow were consistent with fibrotic primary myelofibrosis. We immunohistochemically studied the bone marrow in an attempt to identify a human counterpart to murine segregated-nucleus-containing atypical monocytes. We detected a few CD16+MSR1+CEACAM1+ cells, but not CD14+MSR1+CEACAM1+ cells, by triple immunostaining. The patient is in a good condition and does not require treatment for primary myelofibrosis. Conclusion: There is a possibility that human segregated-nucleus-containing atypical monocytes exist in the bone marrow of primary myelofibrosis patients and might be related to marrow fibrosis. [ABSTRACT FROM AUTHOR]

The article discusses the treatment of polycythaemia vera (PV) with ropeginterferon alfa-2b, focusing on molecular remission and complete haematological response. The study conducted in China showed that a higher initiating dose of ropeg led to a significant anti-neoplastic effect, with patients achieving complete molecular remission and a decrease in JAK2V617F allele burden over time. The treatment was well-tolerated, with a high rate of complete haematological response and a favorable safety profile observed over 24 months. The findings suggest that this treatment regimen may offer robust clinical benefits for patients with PV. [Extracted from the article]

This viewpoint summarizes findings from analyses of large personal patient databases of myeloproliferative neoplasms (MPNs) to assess the impact of thrombosis on mortality, disease progression, and second cancers (SC). Despite advances, the current incidence of arterial and venous thrombosis remains a challenge. These events appear to signal a more aggressive disease course, as evidenced by their association with myelofibrosis progression and mortality using multistate models and time-dependent multivariable analysis. Inflammatory biomarkers, such as the neutrophil-to-lymphocyte ratio (NLR), are associated with the aggressiveness of polycythemia vera (PV) and essential thrombocythemia (ET), linking thrombosis to SC risk. This suggests a common inflammatory pathway likely influencing cardiovascular disease and cancer incidence. Notably, this is observed more frequently in younger patients, likely due to prolonged exposure to MPN and environmental inflammatory triggers. These data underscore the need for new studies to validate these associations, delineate the sequence of events, and identify therapeutic targets to mitigate thrombotic events and potentially improve overall patient outcomes in MPN. [ABSTRACT FROM AUTHOR]

Myelofibrosis (MF) is a complex myeloproliferative neoplasm characterized by abnormal hematopoietic stem cell proliferation and subsequent bone marrow (BM) fibrosis. First documented in the late 19th century, MF has since been extensively studied to unravel its pathophysiology, clinical phenotypes, and therapeutic interventions. MF can be classified into primary and secondary forms, both driven by mutations in genes such as JAK2, CALR, and MPL, which activate the JAK-STAT signaling pathway. These driver mutations are frequently accompanied by additional non-driver mutations in genes like TET2, SRSF2, and TP53, contributing to disease complexity. The BM microenvironment, consisting of stromal cells, extracellular matrix, and cytokines such as TGF-β and TNF-α, plays a critical role in fibrosis and aberrant hematopoiesis. Clinically, MF manifests with symptoms ranging from anemia, splenomegaly, and fatigue to severe complications such as leukemic transformation. Splenomegaly, caused by extramedullary hematopoiesis, leads to abdominal discomfort and early satiety. Current therapeutic strategies include JAK inhibitors like Ruxolitinib, which target the JAK-STAT pathway, alongside supportive treatments such as blood transfusions, erythropoiesis-stimulating agents and developing combinatorial approaches. Allogeneic hematopoietic stem cell transplantation remains the only curative option, though it is limited to younger, high-risk patients. Recently approved JAK inhibitors, including Fedratinib, Pacritinib, and Momelotinib, have expanded the therapeutic landscape. Spatially Resolved Transcriptomics (SRT) has revolutionized the study of gene expression within the spatial context of tissues, providing unprecedented insights into cellular heterogeneity, spatial gene regulation, and microenvironmental interactions, including stromal-hematopoietic dynamics. SRT enables high-resolution mapping of gene expression in the BM and spleen, revealing molecular signatures, spatial heterogeneity, and pathological niches that drive disease progression. These technologies elucidate the role of the spleen in MF, highlighting its transformation into a site of abnormal hematopoietic activity, fibrotic changes, and immune cell infiltration, functioning as a "tumor surrogate." By profiling diverse cell populations and molecular alterations within the BM and spleen, SRT facilitates a deeper understanding of MF pathophysiology, helping identify novel therapeutic targets and biomarkers. Ultimately, integrating spatial transcriptomics into MF research promises to enhance diagnostic precision and therapeutic innovation, addressing the multifaceted challenges of this disease. [ABSTRACT FROM AUTHOR]

The document explores inter-racial genetic differences in myelofibrosis, focusing on a diverse inner-city center analysis. The study conducted at Montefiore Medical Center in the Bronx, NY, with a predominantly Hispanic and Black population, aimed to identify high-risk mutations and their impact on clinical outcomes in a multi-ethnic cohort. Results showed higher prevalence of high molecular risk mutations in non-White patients, particularly Black and Hispanic cohorts, but no significant differences in leukemic transformation or overall survival between racial groups. The study highlights the importance of validating mutational risk profiles in diverse populations and calls for further investigation with larger-scale studies. [Extracted from the article]

ABSTRACT Spleen volume reduction (SVR) is a key endpoint in inhibitors of Janus kinase (JAK) inhibitor studies. Retrospective analyses have demonstrated an association between SVR and improved overall survival (OS) among patients treated with ruxolitinib with a platelet count > 100 × 109/L. Whether this association occurs in patients with thrombocytopenia is unclear. Pacritinib, a JAK2/IRAK1/ACVR1 inhibitor, demonstrated improved SVR versus best available therapy (BAT [best available therapy]; including ruxolitinib) in patients with myelofibrosis and platelet counts ≤ 100 × 109/L in the PERSIST‐2 study. Patients on study at the start of the 12‐week SVR window on pacritinib 200 mg twice daily or BAT were included. OS was evaluated among SVR responders versus non‐responders using different SVR thresholds (≥ 35%, ≥ 20%, ≥ 10%, and > 0%). Among patients on pacritinib (n = 89), SVR ≥ 10% demonstrated the greatest separation in OS curves between responders and non‐responders (HR, 0.00; 95% CI, 0.00–0.14; p < 0.01), though SVR ≥ 0% and SVR ≥ 20% were also associated with improved OS. No SVR threshold conferred OS benefit on BAT (n = 84), including ruxolitinib (n = 39). In patients with myelofibrosis and platelets ≤ 100 × 109/L, achieving SVR on pacritinib, but not BAT (including ruxolitinib), was associated with significant OS benefit, suggesting that pacritinib may offer a unique survival advantage in patients with myelofibrosis and thrombocytopenia who achieve any SVR.Trial Registration: ClinicalTrials.gov number: NCT02055781 [ABSTRACT FROM AUTHOR]

Introduction: Myelofibrosis (MF) is a clonal hematological disorder characterized by bone marrow fibrosis, splenomegaly, and inflammatory cytokine dysregulation. While the role of steroids in MF is not fully defined, their anti-inflammatory properties may offer therapeutic benefits, particularly in managing anemia and other cytopenias. Steroids exert their effects by suppressing pro-inflammatory cytokines such as IL1, IL6, and TNF, and by enhancing anti-inflammatory cytokines like IL4 and IL10. Elevated levels of IL6 and other cytokines in MF are associated with anemia and poor prognosis, suggesting that steroid therapy could mitigate these effects. Areas covered: In this manuscript, we review clinical studies which evaluated the safety and efficacy of steroids in MF patients. Moreover, we examine clinical data of the combination of steroids with immunomodulatory agents and JAK inhibitors. Our literature search consisted of an extensive review of PubMed and clinicaltrials.gov. Expert opinion: The role of steroids in the management of MF remains poorly defined, though emerging evidence suggests a potential therapeutic benefit, particularly in managing anemia and other cytopenias. The combination with IMIDs has also yielded positive outcomes as demonstrated in several studies. Steroids may also play a crucial role in managing cytopenias in MF patients receiving JAKi. [ABSTRACT FROM AUTHOR]

Inflammation plays a pivotal role in the pathogenesis of primary and post-essential thrombocythemia or post-polycythemia vera myelofibrosis (MF) in close cooperation with the underlying molecular drivers. This inflammatory state is induced by a dynamic spectrum of inflammatory cytokines, although recent evidence points to the participation of additional soluble inflammatory mediators. Damage-associated molecular patterns (DAMPs) represent endogenous signals released upon cell death or damage which trigger a potent innate immune response. We assessed the contribution of two prototypical DAMPs, HMGB1 and S100A8/A9, to MF inflammation. Circulating HMGB1 and S100A8/A9 were elevated in MF patients in parallel to the degree of systemic inflammation and levels increased progressively during advanced disease stages. Patients with elevated DAMPs had higher frequency of adverse clinical features, such as anemia, and inferior survival, suggesting their contribution to disease progression. Monocytes, which are key players inMF inflammation, were identified as a source of S100A8/A9 but not HMGB1 release, while both DAMPs correlated with cell death parameters, such as serumLDH and cell-free DNA, indicating that passive release is an additional mechanism leading to increased DAMPs. HMGB1 and S100A8/A9 promote inflammation through binding to Toll-like receptor (TLR) 4, whereas the former also binds TLR2. Monocytes from MF patients were shown to be hyperactivated at baseline, as reflected by higher CD11β and tissue factor exposure and increased expression levels of proinflammatory cytokines IL-1β and IL-6. Patient monocytes showed preserved TLR4 and TLR2 expression and were able to mount normal or even exacerbated functional responses and cytokine upregulation following stimulation of TLR4 and TLR2. Elevated levels of endogenous TLR ligands HMGB1 and S100A8/A9 coupled to the finding of preserved or hyperreactive TLR-triggered responses indicate that DAMPs may promote monocyte activation and cytokine production in MF, fueling inflammation. Plasma IL-1β and IL-6 were elevated in MF and correlated with DAMPs levels, raising the possibility that DAMPs could contribute to cytokine generation in vivo. In conclusion, this study highlights that, in cooperation with classic proinflammatory cytokines, DAMPs represent additional inflammatory mediators that may participate in the generation of MF inflammatory state, potentially providing novel biomarkers of disease progression and new therapeutic targets. [ABSTRACT FROM AUTHOR]

Myeloproliferative neoplasms are stem cell–driven cancers associated with a large burden of morbidity and mortality. Most patients present with early-stage disease, but a substantial proportion progress to myelofibrosis or secondary leukemia, advanced cancers with a poor prognosis and high symptom burden. Currently, it remains difficult to predict progression, and therapies that reliably prevent or reverse fibrosis are lacking. A major bottleneck to the discovery of disease-modifying therapies has been an incomplete understanding of the interplay between perturbed cellular and molecular states. Several cell types have individually been implicated, but a comprehensive analysis of myelofibrotic bone marrow is lacking. We therefore mapped the cross-talk between bone marrow cell types in myelofibrotic bone marrow. We found that inflammation and fibrosis are orchestrated by a "quartet" of immune and stromal cell lineages, with basophils and mast cells creating a TNF signaling hub, communicating with megakaryocytes, mesenchymal stromal cells, and proinflammatory fibroblasts. We identified the β-galactoside–binding protein galectin-1 as a biomarker of progression to myelofibrosis and poor survival in multiple patient cohorts and as a promising therapeutic target, with reduced myeloproliferation and fibrosis in vitro and in vivo and improved survival after galectin-1 inhibition. In human bone marrow organoids, TNF increased galectin-1 expression, suggesting a feedback loop wherein the proinflammatory myeloproliferative neoplasm clone creates a self-reinforcing niche, fueling progression to advanced disease. This study provides a resource for studying hematopoietic cell–niche interactions, with relevance for cancer-associated inflammation and disorders of tissue fibrosis. Editor's summary: Myeloproliferative neoplasms can transition to advanced cancers with poor prognosis. Predicting progression and reversing the associated myelofibrosis remain difficult. Li, Colombo, and Wang et al. present a mouse cancer-stroma interactome for myelofibrosis and show that galectin-1 is a potential inflammation-related target for treating disease. Mesenchymal stem cells, eosinophils, basophils, and mast cells were each implicated in an inflammatory niche that drove myelofibrosis progression. Inhibiting galectin-1 with a monoclonal antibody in a mouse model of myeloproliferative neoplasm decreased fibrosis and cell proliferation and had a beneficial effect on survival. Galectin-1 was associated with myelofibrosis and poor survival in multiple human cohorts. These results suggest that galectin-1 may be a target to alter the inflammatory niche and to reduce fibrosis in myeloproliferative neoplasms. —Brandon Berry [ABSTRACT FROM AUTHOR]

Recurrent problems of patients with myelofibrosis (MF) are cytopenias, debiliating disease-related symptoms and splenomegaly. Whereas the latter are usually addressed by the JAK1/2 inhibitors ruxolitinib and fedratinib, cytopenias often remain critical. Momelotinib, a JAK1/2 inhibitor recently approved for the treatment of anemic MF patients, was shown to improve anemia via a direct inhibition of activin A receptor type I. In this German-wide, multicenter, retrospective analysis the safety and efficacy profile of momelotinib was evaluated in a real world setting within a cohort of 60 MF patients independent of pre-treatment. The median duration of treatment was 12 weeks. As a new, but manageable safety finding, creatinine increase (CTC°1–2) was detected in 10/60 patients (17%). Interestingly, not only hemoglobin levels increased in 84% of patients, but also platelet values (67%). In the cohort of transfusion-dependent individuals (n = 38), transfusion requirement improved in 15 patients (39%) with 8 reaching transfusion independency (21%). Transfusion independency was achieved within a median of 4 weeks (range 2–12). Spleen size decreased in 13/53 individuals (25%) with a median response time of 6 weeks. Thereof, 11 patients had been pre-treated with JAK inhibitor(s) (85%). Clinical improvement was detected in 24/51 symptomatic individuals (47%) with a median response time of 4 weeks. 5 patients stopped treatment due to side effects (8%), 6 patients due to a worsening of clinical symptoms (10%). Taken together, the MoReLife analysis identifies momelotinib as potent and safe therapeutic option also for heavily pre-treated cytopenic MF patients under real world conditions. [ABSTRACT FROM AUTHOR]

The article discusses the use of ruxolitinib after fedratinib failure in patients with myelofibrosis. It presents a case series of 14 patients who received ruxolitinib after fedratinib therapy, detailing their clinical outcomes and responses. The study highlights the potential clinical benefit of second-line ruxolitinib, achieving spleen and symptoms response in a subset of patients. The findings suggest that sequential use of ruxolitinib after fedratinib may be beneficial for selected patients, with no observed excess toxicity in the second-line setting. [Extracted from the article]

Simple Summary: Primary myelofibrosis and secondary myelofibrosis after polycythemia vera and essential thrombocythemia are sub-entities of myeloproliferative neoplasms with poor prognosis for long-term survival. Allogeneic stem-cell transplantation remains the only potentially curative therapy, but the risk of serious side effects and possible treatment-related mortality must be considered. In recent years, efforts have been made to optimize conditioning therapy, donor selection, and supportive therapy in order to improve the outcomes of stem-cell transplantation. We report on 36 patients with myelofibrosis who underwent stem-cell transplantation in our center. We compared the outcomes in earlier and more recent years and evaluated the influence of certain transplant- and patient-specific variables. Pretreatment with a JAK inhibitor, intensified conditioning, and the preferential use of haploidentical instead of mismatched unrelated donors for patients lacking an HLA-identical donor are most likely responsible for the improved outcome after allogeneic stem-cell transplantation in myelofibrosis in recent years. (1) Background: Allogeneic hematopoietic stem-cell transplantation (allo-HSCT) is the only treatment with the potential for cure in patients with myelofibrosis (MF). However, the risk of graft rejection, which is particularly high in MF, and the risk of significant non-relapse mortality must be considered. (2) Methods: In this retrospective, single-center study, we compared allo-HSCT outcomes in 36 adult patients with MF transplanted at two-time intervals (2001–2015 versus 2016–2021). (3) Results: The estimated median overall survival was 48.9 months (95%CI 0.00–98.2) in the cohort transplanted before 2016 and not reached in the more recent years (p = 0.04) due to markedly lower non-relapse mortality (p = 0.02). The 3-year relapse incidence was low in both cohorts (11.1% and 12.5%, p > 0.99). When comparing only subgroups within the more recent cohort based on the presence or absence of total body irradiation (TBI) or the use of sequential regimens, OS and PFS were comparable. (4) Conclusion: Pretreatment with ruxolitinib, intensified conditioning, and the preferential use of haploidentical related instead of mismatched unrelated donors for patients lacking an HLA-identical donor are most likely responsible for the improved outcome after allo-HCT in MF in recent years. [ABSTRACT FROM AUTHOR]

Summary Ruxolitinib is a JAK1/JAK2 inhibitor approved for the treatment of myelofibrosis (MF)‐related splenomegaly or symptoms. The recommended starting dose depends on platelet count, regardless of haemoglobin level at baseline. In the recent years, an overall survival (OS) advantage was reported in patients treated with ruxolitinib compared with best available therapy. We analysed a large Italian cohort of 3494 patients identified by Agenzia Italiana del Farmaco (AIFA) monitoring registries. Of them, 2337 (66.9%) started at reduced dose: these patients were older (median age 70 vs. 67), with increased incidence of large splenomegaly (longitudinal diameter 20 vs. 19.1 cm, median volume 1064 cm3 vs. 1016 cm3), with higher IPSS risk (30.9% vs. 26.1%), and worse ECOG score (more than 1 in 14.3% vs. 9.8%). After balancing for baseline characteristics, Kaplan–Meier analysis showed a median OS of 78.2 months (95% CI 65.9–89) for patients who started at full dose and 52.6 (95% CI 49–56.6) months for patients who started with reduced dose (p < 0.001). Group analysis also showed a substantial difference in patients with intermediate‐2 and high IPSS risk. The majority of MF patients in real‐world analysis started with a reduced dose of ruxolitinib, which is associated with less favourable outcomes. [ABSTRACT FROM AUTHOR]

This document presents a study on the effectiveness of the AAA model in predicting outcomes for patients with essential thrombocythemia (ET), a type of blood cancer. The AAA model incorporates age, arterial hypertension, and anemia to assess the risk of adverse events in ET patients. The study found that the AAA model accurately predicted overall survival and was associated with the risk of thrombosis and major bleeding in ET patients. However, the study acknowledges the limitations of a retrospective analysis and the relatively small number of patients and short follow-up time. [Extracted from the article]

Purpose of Review: Myelofibrosis (MF) includes prefibrotic primary MF (pre-PMF), overt-PMF and secondary MF (SMF). Median overall survival (OS) of pre-PMF, overt-PMF and SMF patients is around 14 years, seven and nine years, respectively. Main causes of mortality are non-clonal progression and transformation into blast phase. Recent Findings: Discoveries on the impact of the biological architecture on OS have led to the design of integrated scores to predict survival in PMF. For SMF, OS estimates should be calculated by the specific MYSEC-PM (MYelofibrosis SECondary-prognostic model). Information on the prognostic role of the molecular landscape in SMF is accumulating. Crucial treatment decisions for MF patients could be now supported by multivariable predictive algorithms. OS should become a relevant endpoint of clinical trials. Summary: Prognostic models guide prediction of OS and treatment planning in MF, therefore, their timely application is critical in the personalized approach of MF patients. [ABSTRACT FROM AUTHOR]

Introduction: In recent years, fedratinib, a selective JAK2 inhibitor, has emerged as a potential therapeutic option for patients who have failed or are intolerant to ruxolitinib. Despite the promising results observed in clinical studies, real-world evidence from the USA and Europe suggests that the efficacy of fedratinib may be less conclusive. We report the characteristics, treatment patterns, and clinical outcomes of patients with myelofibrosis (MF) treated with fedratinib following ruxolitinib failure in Israel’s clinical practice. Methods: This retrospective patient chart review included adults with a physician-reported diagnosis of MF, who initiated fedratinib after discontinuing ruxolitinib. Descriptive analyses characterized patient characteristics, clinical outcomes, and treatment patterns from MF diagnosis through ruxolitinib and fedratinib treatment. Results: We extracted data for 16 eligible patients. Approximately 62.5% of the patients were female, and the median age was 77 (range: 63–85) years. The median duration of ruxolitinib therapy was 17 months (range: 3–84) months. Before the initiation of fedratinib, the median spleen size by palpation was 15.5 cm below the costal margin (range: 4–22 cm). After 3 months the median spleen size was 13 cm below the costal margin (range: 2–21 cm). Only 2 patients showed minimal improvement after 6 months, while 3 patients progressed, and 2 patients showed no change in the spleen size. The spleen response did not improve after 12 months of treatment. At this point, the median spleen size was 19 cm below the costal margin (range: 2–30 cm). Regarding the MF-related symptoms, 43.75% (n = 7) of patients reported some improvement, 37.5% (n = 6) showed no changes, whereas 18.75% (n = 3) of the population complained of worsening. Gastrointestinal toxicity was the most frequent adverse effect of the drug, while 31% of patients died. Conclusion: Our observations showed that in MF patients who have failed to ruxolitinib, the therapeutic value from fedratinib may be modest, especially when exposure time to ruxolitinib was more than 12 months. Early switching from ruxolitinib to fedratinib may yield a better result. [ABSTRACT FROM AUTHOR]

Background: Myelofibrosis (MF) is a myeloproliferative neoplasm characterized by bone marrow fibrosis associated with substantial morbidity and mortality. The therapeutic landscape for MF has advanced with the development of Janus kinase inhibitors (JAKis) like ruxolitinib (RUX), fedratinib (FED), pacritinib (PAC), and momelotinib (MMB), aiming to alleviate symptoms and enhance patient comfort. Methods: A network meta-analysis was conducted to assess the efficacy and safety of eleven JAKi treatment regimens across nine randomized controlled trials (RCTs) with a total of 2340 participants. Outcomes were evaluated in terms of spleen volume reduction (SVR), total symptom score reduction (TSSR), hematological safety profiles, and overall survival (OS). Results: RUX and MMB were superior in achieving SVR and TSSR, with significant dose-response relationships observed. PAC and MMB were associated with a decreased risk of grade 3/4 anemia and thrombocytopenia compared to other JAKis. However, no substantial benefits in OS were observed with newer JAKis compared to RUX. The poorer OS outcomes with certain PAC dosages were likely influenced by baseline patient characteristics, particularly severe cytopenias. Conclusion: The introduction of JAKis significantly changed the treatment of MF. This meta-analysis reaffirms the core role of RUX and positions MMB as a potentially powerful alternative for treating symptoms and reducing spleen size. Meanwhile, MMB and PAC have a positive effect on anemia in MF while FED is more tolerable for patients with thrombocytopenia. However, it should be noted that these results are influenced by baseline patient characteristics, particularly cytopenias, which affects both management and overall survival. Therefore, there is an urgent need for personalized dosing strategies to optimize the balance between efficacy and safety, with careful consideration of patientspecific factors. [ABSTRACT FROM AUTHOR]

Summary: We describe the clinical phenotype, management strategies and outcomes of 22 patients with autoimmune myelofibrosis (AIMF); median age: 45 years; 77% females; 83% with autoimmune disease, pancytopenia in 32% and transfusion‐requiring anaemia in 59%. All informative cases were negative for JAK2 (n = 18) and CALR/MPL mutations (n = 12). Fourteen of nineteen (74%) evaluable patients achieved complete response (CR) based on the resolution of cytopenias. First‐line treatments included steroids +/− immunosuppressive agents, cyclosporin and mycophenolate with CR in 7 of 13 (54%), 1 of 2 (50%) and 1 of 2 (50%) respectively. Rituximab salvage therapy yielded CR in 4 of 5 (80%) cases. The current study provides information on steroid‐sparing treatments for AIMF. [ABSTRACT FROM AUTHOR]

Refractoriness to standard first-line therapy in immune thrombocytopenia (ITP) should foster additional diagnostic work-up to exclude hematological clonal disease, mostly myelodysplatic syndrome (MDS) or clonal cytopenia of unknown significance (CCUS), which may present with isolated thrombocytopenia of immune or non-immune origin. We herein report on a patient who showed a transient leukoerythroblastic reaction (LEB) associated with bone marrow myelofibrosis upon rompilostim treatment, challenging a diagnosis of primary ITP and requiring additional investigations. RUNX-1-mutated myelodysplastic syndrome was eventually diagnosed. Even though LEB and marrow fibrosis have already been rarely reported during romiplostim treatment for ITP, this is the first case to our knowledge in which a background clonal hematopoiesis was diagnosed and deemed potentially involved in the abnormal response to this thrombopoietin receptor agonist (TPO-RA). [ABSTRACT FROM AUTHOR]

Diagnosis of myeloid neoplasm is currently performed according to the presence of a predetermined set of clinical, morphological, and molecular diagnostic criteria agreed upon by a consensus of experts. Even strictly adhering to these criteria, it is possible to encounter patients who present features that are not easily ascribable to a single disease category. This is the case, e.g., of patients with de novo myeloid neoplasms with features intermediate between primary myelofibrosis (PMF) and chronic myelomonocytic leukemia (CMML). In this study, we retrospectively searched the pathological database of IRCCS Humanitas Research Hospital to identify cases of chronic myeloid neoplasm with monocytosis with a driver mutation of classic myeloproliferative neoplasms (MPN) and showing morphological MPN features. For each case, we assessed all epidemiological, clinical, histopathological, and molecular data. Then, we carried out a literature review, searching for cases with features similar to those of our patients. We retrieved a total of 13 cases presenting such criteria (9 from the literature review and 4 from our institution); in all of them, there was a coexistence of clinical, histopathological, and molecular myelodysplastic and myeloproliferative features. To date, according to current classifications (World Health Organization and International Consensus Classification), given the presence/absence of essential features for PMF or CMML, these patients should be formally diagnosed as myelodysplastic/myeloproliferative neoplasm unclassified/not otherwise specified (U/NOS). This review aims to summarize the features of these difficult cases and discuss their differential diagnosis and their classification according to the novel classifications and the existing literature on overlapping myeloid neoplasms. [ABSTRACT FROM AUTHOR]

Background Allogeneic hematopoietic stem cell transplant for myeloid neoplasms with increased fibrosis is uncommon; morphologic features posttransplant can be concerning for persistent disease. Methods In this retrospective study, we identified 22 patients transplanted for myeloproliferative neoplasms or chronic myelomonocytic leukemia with fibrosis at our institution, and reviewed slides from pretransplant and posttransplant bone marrow biopsies. Clinical features and results of molecular, chimerism, and cytogenetic studies were retrieved from the medical record. Results Pretransplant bone marrow biopsies commonly exhibited hypercellularity, atypical megakaryocytes, and reticulin fibrosis. At day 100, 36% of biopsies had reticulin grade >MF1 and 33% of those tested had positive molecular studies, with no significant associations between day 100 marrow characteristics and molecular profile or peripheral count recovery times. In the 1 year posttransplant biopsies (n = 12), 7 of 9 had negative molecular studies; of these, none had reticulin grade >MF1, 1 had trichrome 1+, 2 had atypical megakaryocytes, and 1 was hypercellular. Conclusions Supporting recent literature, our study indicates that persistent day 100 reticulin fibrosis/collagen deposition does not show an association with day 100 molecular status. Our study additionally provides data for 12 patients with 1 year posttransplant marrow biopsies, with the majority of those lacking either increased fibrosis or molecular evidence of persistent disease. [ABSTRACT FROM AUTHOR]

Dysregulated JAK/STAT hyperactivity is essential to the pathogenesis of myelofibrosis, and JAK inhibitors are the first-line treatment option for many patients. There are four FDA-approved JAK inhibitors for patients with myelofibrosis. Single-agent JAK inhibition can improve splenomegaly, symptom burden, cytopenias, and possibly survival in patients with myelofibrosis. Despite their efficacy, JAK inhibitors produce variable or short-lived responses, in part due to the large network of cooperating signaling pathways and downstream targets of JAK/STAT, which mediates upfront or acquired resistance to JAK inhibitors. Synergistic inhibition of JAK/STAT accessory pathways can increase the rates and duration of response for patients with myelofibrosis. Two recently reported, placebo-controlled phase III trials of novel agents added to JAK inhibition met their primary endpoint, and additional late-stage studies are ongoing. This paper will review role of dysregulated JAK/STAT signaling, biological plausible additional therapeutic targets and the recent advancements in combination strategies with JAK inhibitors for myelofibrosis. [ABSTRACT FROM AUTHOR]

The phase 3b FREEDOM trial (ClinicalTrials.gov: NCT03755518) evaluates efficacy/safety of fedratinib in intermediate- or high-risk myelofibrosis patients with platelet count ≥50 × 109/L, previously treated with ruxolitinib. The trial design included protocol specified strategies to mitigate the risk for gastrointestinal (GI) adverse events (AEs), thiamine supplementation, and encephalopathy surveillance. Due to COVID-19, accrual was cut short with 38 patients enrolled. In the efficacy evaluable population (n = 35), nine (25.7%; 95% confidence interval 12.5–43.3) patients achieved primary endpoint of ≥35% spleen volume reduction (SVR) at end of cycle (EOC) 6; and 22 (62.9%) patients showed best overall response of ≥35% SVR up to end of treatment. Sixteen (44.4%) patients showed ≥50% reduction in total symptom score at EOC6 (n = 36). Compared to previously reported JAKARTA-2 trial, rates of GI AEs were lower, and no patient developed encephalopathy. Overall, FREEDOM study showed clinically relevant spleen and symptom responses with fedratinib, and effective mitigation of GI AEs. [ABSTRACT FROM AUTHOR]

The Philadelphia-negative chronic myeloproliferative neoplasms (MPNs) are clonal hematopoietic stem cell disorders predominantly occurring in elderly, whereas in children and young adults are quite infrequent. Therefore, less is known about clinical presentation, genetic abnormalities, prognosis and best management strategies for this groups of patients. Currently, more cases of younger MPN patients are diagnosed. Nevertheless, diagnosis of MPNs, especially in childhood, may be difficult due to lower incidence of JAK2V617F and CALR mutations and differences in peripheral blood counts between adults and children. Challenges for younger MPN patients are longer life expectances, specific psychosocial need, fertility and pregnancy need and a long term therapy side effect (including second cancers). The most severe MPNs complication is transformation to secondary myelofibrosis (MF) or acute myeloid leukemia (AML). Optimal management of young MPNs remains a challenge as the classical risk scores fail in young MPNs. Moreover, the main objective of young MPNs therapy should be the disease outcome modification. Therefore, international collaborative work between pediatricians and "adult hematologists" is required to measure outcomes and generate protocol of management of young MPNs. [ABSTRACT FROM AUTHOR]

The influence of demographic characteristics and social determinants on cancer outcomes is widely recognized in various malignancies but remains understudied in myelofibrosis (MF). This study aims to investigate social and demographic variables associated with MF survival. We retrospectively reviewed data of biopsy-proven MF patients from the Surveillance, Epidemiology and End Results (SEER) database (2000–2021) and Montefiore Medical Center (2000–2023), an underserved inner-city hospital. The SEER cohort included 5,403 MF patients and was predominantly Non-Hispanic (NH) White (82%) with a median age of 69 years. The age-adjusted incidence rate of MF was 0.32 cases per 100,000 person-years, increasing annually by 1.3% from 2000 to 2021. Two- and five- year overall survival rates were 69% and 42%, respectively. Worse cause-specific survival was associated with older age, male sex, and diagnosis before 2011 (year of Ruxolitinib approval). NH-Black ethnicity, unmarried status and lower median income were independent predictors of worse overall survival. The single-center analysis included 84 cases, with a median age of 66 years. NH-White patients comprised 37% of the sample, followed by NH-Black (28.5%). Two- and five- year overall survival rates were 90% and 61%, respectively, with NH-Black patients exhibiting the lowest median survival, although the difference was not statistically significant. Age was a significant predictor of worse survival in this cohort. NH-Black and Hispanic patients lived in areas with higher socioeconomic and demographic stress compared to NH-White patients. Overall, this study highlights the association of social and demographic factors with MF survival and emphasizes the need for equitable healthcare and further exploration of social-demographic factors affecting MF survival. [ABSTRACT FROM AUTHOR]

Myelofibrosis is a rare and often fatal hematological neoplasm, and the treatment of myelofibrosis-associated anemia remains suboptimal, with no improved therapies. Luspatercept was shown to display some efficacy in a phase 2 clinical trial for Myelofibrosis with anemia, yet relevant research are limited. Threrfore, data from patients diagnosed with refractory anemic primary or post-essential thrombocythemia/polycythemia vera myelofibrosis, who were treated with luspatercept for at least 9 weeks, were retrospectively collected. Eighteen patients with myelofibrosis treated with luspatercept were enrolled. Median age was 68 years (range, 44–80 years), and 27.8% were males. Ten (55.6%) were transfusion-dependent. Ten (55.6%) were Dynamic International Prognostic Scoring System intermediate-1, and eight (44.4%) were intermediate-2. The median follow-up was 7 (4–16) months. Erythroid response occurred in eight patients (44.4%) at week 12, four patients (30.8%) at week 24, and nine (50%) at the end of follow-up. Patients who were transfusion-dependent and not transfusion-dependent had similar HI-E responses, at different time points (P > 0.05). Patients had a significantly higher hemoglobin level at 12 weeks, 24 weeks, and at the end of follow-up, than at baseline (P = 0.001, P = 0.021, and P = 0.005, respectively). Treatment-related adverse events occurred in five (16.7%) patients, with no serious adverse events. Two (11.1%) patients relapsed at weeks 15 and 31. One patient progressed to acute myeloid leukemia. No patients had died by the end of follow-up. Luspatercept induced a good response in patients with anemic myelofibrosis, with a low relapse rate and good tolerance. [ABSTRACT FROM AUTHOR]

Myelofibrosis (MF) is a myeloproliferative neoplasm (MPN) with a poor prognosis, and allogeneic hematopoietic stem cell transplantation (allo-HSCT) is the only treatment with curative potential. Ruxolitinib, a JAK1/2 inhibitor, has shown promising results in improving patients' symptoms, overall survival, and quality of life, and can be used as a bridging therapy to HSCT that increases the proportion of transplantable patients. However, the effect of this and similar drugs on HSCT outcomes is unknown, and the reports on their efficacy and safety in the peri-transplantation period vary widely in the published literature. This paper reviews clinical data related to the use of JAK inhibitors in the peri-implantation phase of hematopoietic stem cell transplantation for primary myelofibrosis and discusses their efficacy and safety. [ABSTRACT FROM AUTHOR]

Aims: Spleen and liver stiffness, investigated by VCTE (Vibration-Controlled Transient Elastography), have been associated with marrow fibrosis in patients with myeloproliferative neoplasms (MPNs). Tissue stiffness can be assessed by shear wave point (pSWE) and bidimensional elastography (2DSWE). Spleen stiffness (SS) values were higher in Myelofibrosis (MF) and Polycythemia Vera (PV) compared to Essential Thrombocythemia (ET). We aimed to identify SWE differences between MPN patients and healthy volunteers; to evaluate specific SWE features in patients with MF, PV and ET; to establish a correlation with bone marrow fibrosis in patients with myeloproliferative disease. Methods: Patients with myeloproliferative disease and healthy volunteers performed evaluation of spleen and liver stiffness (LS) by pSWE and 2DSWE. Results: A total of 218 subjects were included: 143 with myeloproliferative disease (64 MF, 29.4%, 33 PV, 15.1% and 46 ET, 21.1%), and 75 (34.4%) healthy volunteers. Compared to volunteers, MF patients had greater spleen (pSWE 40.9 vs. 26.3 kPa, p < 0.001; 2DSWE 34.9 vs. 20.1 kPa, p < 0.001), and liver stiffness (pSWE 7.72 vs. 5.52 kPa, p < 0.001; 2DSWE 6.96 vs. 5.01 kPa, p < 0.001). In low (0–1) (n = 81, 60.4%) versus high-grade bone marrow fibrosis (2–3) (n = 42, 39.6%), is evident a higher median stiffness in patients with higher grades of fibrosis both for liver (pSWE 5.2 vs. 6.65 kPa; 2DSWE 5.1 vs. 6.05 kPa) and spleen (pSWE 27.2 vs. 37.9 kPa, 2DSWE 21.7 vs 30.75 kPa—p < 0.001 in both). Conclusion: SWE evaluation distinguishes MF patients from HV and ET/PV and may help in MPN diagnosis. LS and SS values are associated with bone marrow fibrosis grade. [ABSTRACT FROM AUTHOR]

The authors present the case of a 39-year-old male with an initial diagnosis of de novo acute myeloid leukemia who, despite complete remission without measurable residual disease after conventional induction chemotherapy, presented with persistent splenomegaly and eosinophilia. As reactive eosinophilia was excluded and CBFB::MYH11 and RUNX1::RUNX1T1 gene fusions were not identified in additional molecular studies, we decided to test for other causes of clonal eosinophilia. Cytogenetic and molecular testing identified FIP1L1::PDGFRA gene fusion and prompted the introduction of imatinib. The initial diagnosis of de novo acute myeloid leukemia was changed to myeloid/lymphoid neoplasm with eosinophilia and FIP1L1::PDGFRA in the blast phase as myeloid blast count in the bone marrow at the diagnosis was >20%. The patient has maintained a complete molecular response with imatinib at a dose of 100 mg for more than two years. [ABSTRACT FROM AUTHOR]

Momelotinib, an oral Janus kinase (JAK) 1/2 and activin A receptor type 1 inhibitor, improved symptoms, splenomegaly, and anemia in patients with myelofibrosis (MF). This sub-analysis of SIMPLIFY-1 evaluated the efficacy and safety of momelotinib versus ruxolitinib in Japanese patients with JAK inhibitor (JAKi)-naïve MF. Patients were randomized 1:1 to receive momelotinib 200 mg once daily or ruxolitinib 20 mg twice daily (or modified based on label) for 24 weeks, after which patients could receive open-label momelotinib. The primary endpoint was splenic response rate (SRR; ≥ 35% reduction in spleen volume) at 24 weeks; main secondary endpoints were total symptom score (TSS) response (≥ 50% reduction) and transfusion independence (TI) rates. Fifteen Japanese patients (momelotinib, n = 6; ruxolitinib, n = 9) were enrolled; all completed treatment. At Week 24, SRR was 50.0% with momelotinib and 44.4% with ruxolitinib. TSS response rates were 33.3% and 0%, and TI rates were 83.3% and 44.4%. Any-grade treatment-related adverse event (TRAE) rates were 83.3% with momelotinib and 88.9% with ruxolitinib. Grade 3/4 TRAE rates were 0% and 55.6%, with specific events being anemia (55.6%) and vertigo (11.1%) with ruxolitinib. Momelotinib was well tolerated, improved spleen and symptom responses, and reduced transfusion requirements in Japanese patients with JAKi-naïve MF. [ABSTRACT FROM AUTHOR]

Introduction: Some Janus kinase (JAK) inhibitors such as ruxolitinib and fedratinib do not address and may worsen anemia in patients with myelofibrosis. In these cases, the JAK inhibitor may be continued at a reduced dose in an effort to maintain splenic and symptom control, with supportive therapy and/or red blood cell (RBC) transfusions added to manage anemia. This post hoc descriptive analysis of the phase 3 SIMPLIFY-2 trial evaluated the relative benefits of this approach versus switching to the JAK1/JAK2/activin A receptor type 1 inhibitor momelotinib in patients for whom anemia management is a key consideration. Methods: SIMPLIFY-2 was a randomized (2:1), open-label, phase 3 trial of momelotinib versus best available therapy (BAT; 88.5% continued ruxolitinib) in JAK inhibitor-experienced patients with myelofibrosis (n = 156). Patient subgroups (n = 105 each) were defined by either baseline (1) hemoglobin (Hb) of < 100 g/L or (2) non-transfusion independence (not meeting the criteria of no transfusions and no Hb of < 80 g/L for the previous 12 weeks); outcomes have been summarized descriptively. Results: In both subgroups of interest, week 24 transfusion independence rates were higher with momelotinib versus BAT/ruxolitinib: baseline Hb of < 100 g/L, 22 (33.3%) versus 5 (12.8%); baseline non-transfusion independent, 25 (34.7%) versus 1 (3.0%). Mean Hb levels over time were also generally higher in both subgroups with momelotinib, despite median transfusion rates through week 24 with momelotinib being comparable to or lower than with BAT/ruxolitinib. Spleen and symptom response rates with momelotinib in these subgroups were comparable to the intent-to-treat population, while rates with BAT/ruxolitinib were lower. Conclusion: In patients with moderate-to-severe anemia and/or in need of RBC transfusions, outcomes were improved by switching to momelotinib rather than continuing ruxolitinib and using anemia supportive therapies. Trial Registration: ClinicalTrials.gov: NCT02101268. Plain Language Summary: Patients with the rare blood cancer myelofibrosis often experience symptoms such as tiredness, an increase in the size of their spleens (an organ involved in filtering the blood), and anemia (too few red blood cells). One type of treatment for myelofibrosis, called a Janus kinase (JAK) inhibitor, can help patients to feel better and reduce the size of their spleens, but some JAK inhibitors do not help with anemia and may make it worse. In those situations, patients may continue to take their JAK inhibitor but also receive another type of treatment, called an anemia supportive therapy, and may also receive red blood cell transfusions. This study compared 2 treatment approaches, continuing the JAK inhibitor ruxolitinib and adding an anemia supportive therapy and/or transfusions versus switching to another treatment called momelotinib, in 2 groups of patients from a clinical trial: (1) patients with levels of hemoglobin (a red blood cell protein) at the start of the trial that indicated that they had anemia, and (2) patients who were already receiving red blood cell transfusions at the start of the trial. In both groups, more patients did not need red blood cell transfusions anymore at week 24 with momelotinib, and their hemoglobin levels on average became higher over time. More patients also had improvements in spleen size and symptoms with momelotinib. Overall, outcomes were improved by switching to momelotinib rather than continuing ruxolitinib and using supportive therapies and/or red blood cell transfusions to treat anemia. [ABSTRACT FROM AUTHOR]

Abstract Myelofibrosis (MF) is a complex myeloproliferative neoplasm characterized by abnormal hematopoietic stem cell proliferation and subsequent bone marrow (BM) fibrosis. First documented in the late 19th century, MF has since been extensively studied to unravel its pathophysiology, clinical phenotypes, and therapeutic interventions. MF can be classified into primary and secondary forms, both driven by mutations in genes such as JAK2, CALR, and MPL, which activate the JAK-STAT signaling pathway. These driver mutations are frequently accompanied by additional non-driver mutations in genes like TET2, SRSF2, and TP53, contributing to disease complexity. The BM microenvironment, consisting of stromal cells, extracellular matrix, and cytokines such as TGF-β and TNF-α, plays a critical role in fibrosis and aberrant hematopoiesis. Clinically, MF manifests with symptoms ranging from anemia, splenomegaly, and fatigue to severe complications such as leukemic transformation. Splenomegaly, caused by extramedullary hematopoiesis, leads to abdominal discomfort and early satiety. Current therapeutic strategies include JAK inhibitors like Ruxolitinib, which target the JAK-STAT pathway, alongside supportive treatments such as blood transfusions, erythropoiesis-stimulating agents and developing combinatorial approaches. Allogeneic hematopoietic stem cell transplantation remains the only curative option, though it is limited to younger, high-risk patients. Recently approved JAK inhibitors, including Fedratinib, Pacritinib, and Momelotinib, have expanded the therapeutic landscape. Spatially Resolved Transcriptomics (SRT) has revolutionized the study of gene expression within the spatial context of tissues, providing unprecedented insights into cellular heterogeneity, spatial gene regulation, and microenvironmental interactions, including stromal-hematopoietic dynamics. SRT enables high-resolution mapping of gene expression in the BM and spleen, revealing molecular signatures, spatial heterogeneity, and pathological niches that drive disease progression. These technologies elucidate the role of the spleen in MF, highlighting its transformation into a site of abnormal hematopoietic activity, fibrotic changes, and immune cell infiltration, functioning as a “tumor surrogate.” By profiling diverse cell populations and molecular alterations within the BM and spleen, SRT facilitates a deeper understanding of MF pathophysiology, helping identify novel therapeutic targets and biomarkers. Ultimately, integrating spatial transcriptomics into MF research promises to enhance diagnostic precision and therapeutic innovation, addressing the multifaceted challenges of this disease.

Background. Currently, targeted therapy is the most promising for the treatment of myelofibrosis (MF). Today, the results of many years of experience with the use of ruxolitinib, including outside randomized trials and the identification of predictors of its effectiveness are important.Aim. To evaluate the results of long-term ruxolitinib therapy in patients with primary and secondary MF resistant to standard treatment and compare the effectiveness of MF targeted therapy in patient groups depending on age, gender, clinical, laboratory and morphological parameters.Materials and methods. The prospective study included 206 patients (95 (46 %) men and 111 (54 %) women aged 18–84 (mean 64) years) with MF in the chronic phase who received ruxolitinib: 154 (75 %) with primary MF, 39 (19 %) – with post-polycythemic, 13 (6 %) – with post-thrombocythemic. The median duration of chronic myeloproliferative disease from diagnosisto prescription of ruxolitinib was 75 (1–432) months. According to DIPSS (Dynamic International Prognostic Scoring System), 15 % of patients were classified as high risk, 35 % as intermediate-2, 33 % as intermediate-1, and 17 % as low-risk. 44 % of patients had MF3, 49 % – MF2, 7 % – MF1. 71 % of patients had JAK2 V617F mutation, 3 % – MPL, 19 % – CALR, and in 7 % triple negative status was detected.Results. The median duration of ruxolitinib therapy was 24 (1–116) months. Clinical and hematological response at 1 month: complete and partial response – 14 %, clinical improvement – 20 %, stabilization – 57 %; at 3 months – 21, 34, 36 %, at 1 year – 34, 21, 34 %, respectively. No response was obtained in 18 % of patients. The median allele burden of JAK2 V617F during observation decreased more than twice from the initial value in half of the patients. The median of progression-free survival (PFS) from the start of ruxolitinib therapy was 28 months, the median of overall survival (OS) has not been achieved. PFS at 1 year of treatment was 68 %, at 2 years – 56 %, at 3 years – 46 %, at 5 years – 32 %, OS – 87, 75, 68, and 54 %, respectively. Among many factors analyzed before starting ruxolitinib therapy, the following ones had statistically proofed significance for PFS: age, DIPSS risk level,therapy with hydroxycarbamide, interferon, white blood cell count, platelet count, hemoglobin level, and degree of fibrosis. For OS,the following factors were significantly important: age, risk level according to DIPSS,type of MF, interferon therapy, white blood cell count, platelet count, hemoglobin level, and degree of fibrosis.Conclusion. The long-term effectiveness of ruxolitinib therapy for primary and secondary MF has been demonstrated. Gender, age, clinical, laboratory, and morphological prognostic factors of ruxolitinib therapy efficiency in MF have been identified.

Purpose of Review: The landscape of myelofibrosis (MF) has changed since the discovery of the JAK2 V617F mutation and subsequent development of JAK inhibitors (JAKis). However, treatment with JAKis remain a challenge. In this review we critically analyze the strengths and limitations of currently available JAK inhibitors. Recent Findings: In MF patients, JAK inhibitors have been associated with reduced symptom burden and spleen size, as well as improved survival. However, durability of response and development of treatment resistance remain an issue. Recently, there has been increased efforts to optimize treatment with the development of highly selective JAK inhibitors, as well as use of combination agents to counter disease resistance through targeting aberrant signaling pathways. Summary: Treatment of MF patients with JAKi therapy can be challenging but the development of more potent and selective JAK inhibitors, as well as combination therapies, represent exciting treatment advances in this field. [ABSTRACT FROM AUTHOR]

Purpose of Review: Allogeneic hematopoietic cell transplantation is the only potentially curative treatment for myelofibrosis. This review discusses issues not well-covered by existing guidelines: timing of transplant, pre-transplant spleen management and alternative donors; providing our approach to these situations. Recent Findings: Research continues to allow better identification, by better risk stratification and advances in understanding likelihood of durable JAKi response, which patients are likely to derive benefit from upfront transplant versus those for whom delayed transplant may be more appropriate. Several options of JAKi therapy provide a non-surgical option for pre-HCT splenomegaly management, allowing some patients to avoid risks associated with splenectomy. Recent years have also seen a sharp spike in haploidentical donor transplants, along with narrowing of the gap in outcomes between donor types. Summary: Continuous enrollment in prospective studies or well-designed registries is required to generate the high-quality data needed to develop better decision tools for these scenarios. [ABSTRACT FROM AUTHOR]

Abstract Myelofibrosis (MF), a complex hematological malignancy, presents a diverse array of symptoms, including anemia, constitutional symptoms, bone marrow insufficiency, and splenomegaly. The latter, often necessitating blood transfusions, poses an essential obstacle to MF management. While conventional approaches predominantly involve the use of JAK inhibitors, the potential for exacerbating anemia introduces complexity to the treatment. Nonetheless, Momelotinib stands out as a promising pharmaceutical compound with the potential to revolutionize the field. Momelotinib is an ACVR1 antagonist and a dual inhibitor of the JAK1 and JAK2 enzymes. By targeting MF's hematological and fibrotic aspects, Momelotinib influences iron metabolism by regulating hepcidin. This results in reduced hepcidin expression and increased iron availability, ultimately leading to improved anemia and reduced dependency on blood transfusion. This study aims to provide a concise overview of the pathogenesis of MF and elucidate the mechanism of action of Momelotinib. Subsequently, our review offers a practical summary encompassing the effects of Momelotinib in monotherapy, combined comparative drug therapy, and its associated side effects. Additionally, we explore the application of Momelotinib in other cancer types and investigate predictors for treatment success. Furthermore, we examine the utilization of Momelotinib in patients with liver and kidney failure.

Abstract Introduction IDH2 mutation is an unfavorable prognostic factor in patients with primary myelofibrosis (PMF) but its effect on myelofibrosis (MF) remains largely unclear. Methods In this study, we aimed to elucidate the roles of IDH2 mutation in the development and progression of MF by transcriptomic and molecular techniques using the Idh2R172K transgenic mice. Results We found that thrombopoietin (TPO)‐overexpressed Idh2R172K (Idh2R172K + TPO) mice had accelerated progression to MF, compared with TPO‐overexpressed Idh2‐wild (WT + TPO) mice, showing activation of multiple inflammatory pathways, among which nuclear factor κB (NFκB) was the most significantly enhanced. Single‐cell transcriptomes of the marrow cells in early MF showed that S100a8/a9 expression was mainly confined to neutrophil progenitors in the WT + TPO mice, but highly expressed in several types of myeloid precursor cells, including the megakaryocyte progenitors in the Idh2R172K + TPO group. Furthermore, Idh2R172K mice at age of 18 months had larger spleens, increased S100a8/a9‐Tlr4 expression, and elevated serum S100a8/a9 levels compared with WT mice. PMF patients with IDH2 mutations had higher bone marrow plasma S100A8/A9 levels than those without IDH2 mutations. Conclusion Overall, our findings showed that IDH2 mutation induced proinflammatory effects, which further exacerbated MF, as evidenced by the increase in S100a8/a9 levels and NFκB hyperactivation in Idh2R172K + TPO mice.

Refractoriness to standard first-line therapy in immune thrombocytopenia (ITP) should foster additional diagnostic work-up to exclude hematological clonal disease, mostly myelodysplatic syndrome (MDS) or clonal cytopenia of unknown significance (CCUS), which may present with isolated thrombocytopenia of immune or non-immune origin. We herein report on a patient who showed a transient leukoerythroblastic reaction (LEB) associated with bone marrow myelofibrosis upon rompilostim treatment, challenging a diagnosis of primary ITP and requiring additional investigations. RUNX-1-mutated myelodysplastic syndrome was eventually diagnosed. Even though LEB and marrow fibrosis have already been rarely reported during romiplostim treatment for ITP, this is the first case to our knowledge in which a background clonal hematopoiesis was diagnosed and deemed potentially involved in the abnormal response to this thrombopoietin receptor agonist (TPO-RA).

Myelofibrosis (MF), a complex hematological malignancy, presents a diverse array of symptoms, including anemia, constitutional symptoms, bone marrow insufficiency, and splenomegaly. The latter, often necessitating blood transfusions, poses an essential obstacle to MF management. While conventional approaches predominantly involve the use of JAK inhibitors, the potential for exacerbating anemia introduces complexity to the treatment. Nonetheless, Momelotinib stands out as a promising pharmaceutical compound with the potential to revolutionize the field. Momelotinib is an ACVR1 antagonist and a dual inhibitor of the JAK1 and JAK2 enzymes. By targeting MF's hematological and fibrotic aspects, Momelotinib influences iron metabolism by regulating hepcidin. This results in reduced hepcidin expression and increased iron availability, ultimately leading to improved anemia and reduced dependency on blood transfusion. This study aims to provide a concise overview of the pathogenesis of MF and elucidate the mechanism of action of Momelotinib. Subsequently, our review offers a practical summary encompassing the effects of Momelotinib in monotherapy, combined comparative drug therapy, and its associated side effects. Additionally, we explore the application of Momelotinib in other cancer types and investigate predictors for treatment success. Furthermore, we examine the utilization of Momelotinib in patients with liver and kidney failure. Highlights: MF is a complex hematological malignancy that has the potential to transform into acute myeloid leukemia in 20 % of cases Anemia occurs in approximately one-third of MF patients Momelotinib is a novel ACVR1 antagonist and a dual inhibitor of the JAK1 and JAK2 enzymes just FDA approved on September 15 A comprehensive applied review of this novel agent is lacking [ABSTRACT FROM AUTHOR]

BCR::ABL1‐negative myeloproliferative neoplasms (MPNs) are clonal haematopoietic stem cell disorders characterized by specific driver mutations and an increased risk of both macrothrombosis and microthrombosis. Serotonin receptor type 1B (HTR1B) was found to be expressed by various solid tumours, and also primary bone marrow mononuclear cells from myelodysplastic neoplasm and acute myeloid leukaemia patients, representing a potential therapeutic target. In this study we assessed for the first time the expression levels of HTR1B mRNA in the peripheral blood mononuclear cells (PBMC) of 85 newly diagnosed MPN patients, consisting of 28 polycythemia vera, 25 essential thrombocythemia and 32 primary myelofibrosis cases. Levels of HTR1B expression between MPN subtypes and control group were not significantly different. However, at clinical data examination, it was observed that MPN patients with a recent history of major thrombosis and/or signs of impaired microcirculation exhibited significantly higher HTR1B expression levels compared to non‐thrombotic MPNs and control group. Moreover, thrombotic MPN patients had significantly higher HTR1B expression than patients with recent thrombosis and absence of MPN diagnostic criteria. These findings suggest that increased levels of HTR1B expression in PBMC might be associated with thrombosis in MPN patients, but larger studies are needed for confirmation, including testing of the receptor protein expression level. [ABSTRACT FROM AUTHOR]

We investigated the role of toll‐like receptors (TLRs) in inflammatory pathways in Philadelphia chromosome‐negative myeloproliferative neoplasms (Ph(−)MPNs). TLR2 expression was increased in ET, PV, and MPN (grouped as (PV + (ET) + MF)), whereas TLR4 was elevated only in MPN. TLR3, 7, and 9 were not elevated. Cultured monocyte‐derived dendritic cells and plasma assays in TLR2‐elevated patients were found to secrete more cytokines than those from TLR2‐normal patients. These facts suggest that TLR2 is the major inflammatory pathways in MPN. We also measured S100A9 and reactive oxygen species (ROS), revealing increased S100A9 in PV, MF, and MPN, while ROS were only increased in MF. These data suggests that MPNs initially involve TLR2, with minor contributions from TLR4, and with S100A9, leading to ROS formation, JAK2 mutation, and progression to MF or leukemia. Furthermore, patients with JAK2 mutations or leukocytosis exhibited higher TLR2 expression. In leukocyte–platelet interactions, cells from MPN patients displayed a stronger response to a TLR2 agonist than TLR4 agonist. A TLR2 inhibitor (but not a TLR4 inhibitor) attenuated this response. Thrombosis incidence was higher in TLR2‐elevated patients (29%) than in TLR2‐normal patients (19%). These findings suggest that TLR2 likely contributes to thrombosis in MPN. [ABSTRACT FROM AUTHOR]

Myelofibrosis (MF) is a clonal disorder of hematopoietic stem cells characterized by altered bone marrow function and fibrosis. The aim of this narrative review is to report on the most recent epidemiologic data and to discuss features of MF and current strategies for the management of this condition in clinical practice. MF features covered by our review will include: characteristics of patients with MF; myeloproliferative and myelodepletive phenotypes; MF-associated thrombosis and bleeding; risk of infections; prefibrotic and overt PMF; secondary MF. Finally, we will discuss a few aspects of MF management in clinical practice and suggest strategies for its optimization and standardization. The focus of our paper is on Italy, but relevant data from other countries will also be reviewed. [ABSTRACT FROM AUTHOR]

Objective: To evaluate the association between JAK2V617F mutation status, PMF disease characteristics, and prognostic features as assessed by the DIPSS scoring system. We analyzed clinical and laboratory data from a cohort of PMF patients to determine the influence of JAK2 mutation on disease presentation and progression. Study Design: Cross Sectional study. Setting: Department of Pathology and Oncology, King Edward Medical University/Mayo Hospital, Lahore. Period: December 2022 to December 2023. Methods: Total 27 patients with PMF were enrolled in the study by non-probability consecutive sampling technique. Patients were diagnosed according to WHO 2016 criteria. CBC and serum LDH were performed by automated hematology and chemistry analyzers respectively. Real-time PCR was used to identify the JAK2 mutations. Risk stratification was done by DIPSS criteria. Data was analyzed by SPSS 28. Mean and standard deviation was calculated. Student 'T' test was used for comparison of mean between two groups with and without JAK2V617F mutations. Results: Out of 27 patients 66.6% were males and median age was 59 years. Splenomegaly was the dominant clinical feature accounting for 51.4% with mean splenic span of 17.8±2.91cm. Mean LDH levels was 872.5±324. JAK2 positive expression was found to be significantly correlated with increased splenic span and raised LDH levels with P-value of <0.05. Risk stratification showed 11% patients were in high-risk group. Conclusion: Marked enlargement of spleen and raised in serum LDH levels indicate that patients in our settings had clinically advanced stage of the disease. Apart from this manifestation of JAK2 V617F mutated patients indicated a more aggressive phenotype of the disease. [ABSTRACT FROM AUTHOR]

The article discusses the presence and characteristics of NFE2 mutations in myeloid neoplasms, including myelodysplastic syndromes (MDS), myeloproliferative neoplasms (MPN), and acute myeloid leukemia (AML). The study found that NFE2 mutations were most common in MPN and MDS, and were associated with elevated NFE2 mRNA expression levels in MPN. The mutations may also play a role in the development of bone marrow fibrosis in MPN and MDS. Further research is needed to fully understand the impact of NFE2 mutations on disease progression and transformation to leukemia. [Extracted from the article]